Objectives:

Primary

• To determine the safety and tolerability of escalating doses of RU-101 for 4 weeks in patients with severe dry eye

Secondary

• To explore the efficacy of RU-101
• To explore optimal endpoints for future studies

This is a Phase 1/2, first-in-human, multicenter, dose escalation, double-masked, placebo controlled study consisting of two stages. In Stage I, 3 cohorts are planned to evaluate escalating doses of RU 101 ophthalmic solution, instilled 6 times daily into each eye for 4 weeks (28 days). Each cohort will comprise 4 patients randomized 3:1 to RU-101 or placebo. A masked safety data review will be performed prior to each dose escalation to determine if any dose limiting toxicities (DLTs) occurred and to define the MTD or highest dose to be used in Stage II. In Stage II, an expanded cohort will receive the dose defined in Stage I (MTD or highest dose if MTD is not reached), instilled 6 times daily into each eye for 12 weeks (84 days). The expanded cohort will comprise approximately 96 patients randomized 1:1 to RU-101 or placebo, provided in a double-masked manner.

Inclusion Criteria:

1. Male or female patients aged 18 to 80 years.

2. Patients have had dry eye symptoms at least 4 months.

3. Patients have the following signs in the worst eye:

   1. Corneal staining score with fluorescein staining ≥ 6/15 with at least one in the central
   2. Conjunctival staining score with Lissamine Green ≥ 2/18

4. Patients who had been receiving treatment with eye drops of artificial tears, Restasis, or topical steroids but have had insufficient efficacy or have found these products to be intolerable. If using Restasis or topical steroids, patients must agree to a 30-day washout period prior to the first IP dose (Day 0).

5. Female patients of child bearing potential must agree to have a urine pregnancy test performed at Screening (must be negative) and agree to use a medically acceptable form of birth control (e.g., intrauterine device, birth control pill, patch or subcutaneous implant, condoms, diaphragm, or abstinence) throughout the duration of IP instillation. Women considered capable of becoming pregnant include all females who have experienced menarche and who have not experienced menopause (as defined by amenorrhea for > 12 consecutive months) or have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy).

Exclusion Criteria:

1. Presence of anterior eye diseases except dry eye.
2. Intraocular pressure ≥ 22 mmHg at Screening.
3. Use of any ophthalmic solutions (including over-the-counter [OTC] solutions), serum eye drops, or contact lenses during the Treatment Phase. Artificial tears are allowed during the Screening Phase but must not be used from the first dose (Day 0) through the Treatment Phase.
4. Use of eye drops of Restasis or topical steroids within 30 days of the first dose (Day 0).
5. Use of antihistamines, beta blockers, tricyclic antidepressants, or antidepressants with anticholinergic side effects during the Treatment Phase.
6. Patients with previous corneal transplantation or laser-assisted in situ keratomileusis (LASIK).
7. Presence of graft-versus-host disease (GVHD).
8. Patients who have had other ocular surgery within 3 months prior to the first dose.
9. Patients with punctal plugs or punctal cautery < 3 months prior to the first dose.
10. Patients with severe dry eye due to Stevens-Johnson disease or ocular cicatricial pemphigoid.
11. History of allergy to human serum protein products and/or any history of allergy to yeast.
12. History of allergies to recombinant products, ophthalmic solutions, any constituents of RU 101, or any solutions planned for use in this study.
13. Any significant chronic illness that, in the opinion of the Principal Investigator (PI), could interfere with the study parameters.
14. Use of any investigational product or device within 30 days prior to the Screening Visit or during the study.
15. Known history of alcohol and/or drug abuse within the past 12 months, which in the opinion of the PI could interfere with study compliance, outcome measures including safety parameters, and/or the general medical condition of the patient.
16. Those unable in the opinion of the PI to comply fully with the study requirements.